Download Phantom limb pain: a case of maladaptive CNS plasticity?

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Phantom limb pain: a case of
maladaptive CNS plasticity?
Herta Flor*, Lone Nikolajsen‡ and Troels Staehelin Jensen§
Abstract | Phantom pain refers to pain in a body part that has been amputated or
deafferented. It has often been viewed as a type of mental disorder or has been assumed
to stem from pathological alterations in the region of the amputation stump. In the past
decade, evidence has accumulated that phantom pain might be a phenomenon of the CNS
that is related to plastic changes at several levels of the neuraxis and especially the cortex.
Here, we discuss the evidence for putative pathophysiological mechanisms with an emphasis
on central, and in particular cortical, changes. We cite both animal and human studies and
derive suggestions for innovative interventions aimed at alleviating phantom pain.
*Department of Clinical and
Cognitive Neuroscience,
University of Heidelberg,
Central Institute of Mental
Health, D-68159 Mannheim,
Germany. ‡Department of
Anesthesiology and Danish
Pain Research Center,
§
Department of Neurology
and Danish Pain Research
Center, Aarhus University
Hospital, DK-8000 Aarhus C,
Denmark.
Correspondence to H.F.
e-mail:
[email protected]
doi:10.1038/nrn1991
The amputation or deafferentation of a limb or another
body part is usually followed by a global feeling that the
missing limb is still present (phantom limb awareness),
as well as specific sensory and kinaesthetic sensations
(phantom sensations)1. These non-painful phantom
phenomena are reported by almost all amputees 2.
Phantom limb pain, or phantom pain, belongs to a group
of neuropathic pain syndromes that is characterized by
pain in the amputated limb or pain that follows partial
or complete deafferentation. Phantom pains have also
been observed as a consequence of the loss of other
body parts such as the breast3, and can occur following
spinal cord injury4,5. Residual limb (or stump) pain and
non-painful residual limb phenomena are sensations in
the still-present body part adjacent to the amputation or
deafferentation line.
Phantom pain has many features: at one end of the
spectrum it is limited to simple, short-lasting and rarely
occurring painful shocks in a missing body part; at the
other end of the spectrum it can be a constant, excruciatingly painful experience during which the individual has
a vivid and intense perception of the missing body part.
It seems to be more severe in the distal portions of the
phantom and can have a number of characteristics such
as stabbing, throbbing, burning or cramping6. Its onset
can be immediate, but it may also appear for the first
time many years after the amputation2.
Several factors can affect the occurrence and extent of
phantom pain. Pre- and postoperative pain can influence
subsequent phantom limb pain, and it can be difficult
to differentiate postoperative, residual limb and phantom limb pain, especially in the early post-amputation
phase. Perioperative pain management has improved
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during the past two decades and now includes both
peripheral and central analgesia, but this change in
treatment strategy has not resulted in a corresponding
reduction of phantom pain2; phantom limb pain still
occurs in 50–80% of amputees irrespective of whether
the amputation is traumatic or performed for medical
reasons, and therefore remains a significant problem7,8.
In Western countries, the main reason for amputation
is chronic vascular disease. The patients are elderly and
have often suffered from long-lasting pre-amputation
pain. In other parts of the world, civil wars and landmine
explosions result in many unfortunate cases of traumatic
amputations in otherwise healthy people9. It is possible
that the occurrence and nature of phantom limb pain
might differ depending on whether amputation was carried out for chronic or traumatic reasons, although so
far there are insufficient data to draw firm conclusions
about this7. Interestingly, phantom limb pain is more
frequent when the amputation occurs in adulthood,
less frequent in child amputees and virtually non-existent
in congenital amputees10,11. Phantom limb pain could be
related to a certain position or movement of the phantom, and might be elicited or exacerbated by a range of
physical factors (for example, changes in the weather or
pressure on the residual limb) and psychological factors
(for example, emotional stress)12.
The long-term course of phantom limb pain is unclear.
Whereas some authors report a slight decline in pain
prevalence over the course of several years13, others have
described high prevalence rates in long-term amputees8.
As discussed below, central as well as peripheral factors
have been implicated as determinants of phantom limb
pain: the clinical characteristics of phantom pain and
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empirical data on central factors, including reports on the
effect of brain lesions on phantoms14, suggest that it cannot be completely explained by peripheral mechanisms2.
Psychological factors such as anxiety or depression do
not seem to be a primary cause, but they might well affect
the onset, course and the severity of the pain6,8. Here,
we review evidence that has accumulated over the past
decade showing that multiple changes along the neuraxis
contribute to the experience of phantom limb pain and
that cortical changes have a special role.
Neuroma
When a limb is severed, a
terminal swelling or ‘endbulb’
is formed and axonal sprouting
occurs. In the case of an
amputation, sprouting and
endbulb formation lead to a
neuroma, a tangled mass that
forms when the axons
cannot reconnect or can only
partially reconnect, as is the
case in partial lesions. These
neuromas generate abnormal
activity that is called ectopic
because it does not originate
from the nerve endings.
Dorsal root ganglion
A nodule on a dorsal root that
contains cell bodies of afferent
spinal neurons, which convey
somatosensory input to the
CNS.
Paraesthesia
An abnormal skin sensation
such as tingling or itching.
Peripheral changes
Amputees often report pain and sensitivity to vibration
and touch in the nerve that innervated the amputated
limb or in the residual limb adjacent to the amputation
line. A classic feature following complete or partial nerve
injury is the presence of the Tinel sign, which refers
to the local or referred pain (pain in the innervation
territory of the damaged nerve) that occurs in response
to brief mechanical stimulation of an injured nerve.
Similarly, tapping of stump neuromas can cause pain in
the phantom limb and in the stump2.
Following experimental injury to nerves, axotomized
afferent neurons show retrograde degeneration and
shrinking, primarily involving unmyelinated neurons15.
As a consequence of injury, terminal swelling and
regenerative sprouting of the injured axon end occurs
and neuromas form in the residual limb that display
spontaneous and abnormal evoked activity to mechanical and chemical stimuli16. Ectopic discharges from
stump neuromas represent a source of abnormal afferent
input to the spinal cord and a potential mechanism for
spontaneous pain and abnormal evoked pains17. Ectopic
discharge from myelinated axons seems to begin earlier
and tends to be rhythmic, whereas C-fibres tend to show
slow, irregular patterns18. The increased excitability of
injured nerves that results in ectopic discharge seems
to be due to alterations in the electrical properties
of cellular membranes. These alterations involve the
upregulation or novel expression, and altered trafficking, of voltage-sensitive sodium channels and decreased
potassium channel expression, as well as altered transduction molecules for mechano-, heat and cold sensitivity in the neuromas19,20. In addition, experimental injury
causes the expression of novel receptors in the neuroma
that are sensitive to cytokines, amines and so on, which
might enhance nociceptive processing18. Non-functional
connections between axons (ephapses) might also
contribute to the spontaneous activity21.
Nyström and Hagbarth22 carried out a classic microneurographic study in which tapping of neuromas in
two amputees was associated with increased activity
in afferent C-fibres and an increased pain sensation.
They also found that anaesthetic blockade of neuromas
eliminated spontaneous and stimulation-induced nerve
activity related to the stump, but not ongoing phantom limb pain. Moreover, phantom limb pain is often
present soon after amputation, before a palpable, swollen
neuroma could have formed2. These findings motivated
a search for other potential sources of ectopic activity in
the PNS that are more proximal to the residual limb.
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An additional site of ectopic discharge is the dorsal
(DRG). Ectopic discharges originating
in the DRG can summate with ectopic activity from
neuromas in the stump. Indeed, processes such as crossexcitation can lead to the depolarization and activation
of neighbouring neurons, significantly amplifying the
overall ectopic barrage18. Spontaneous as well as triggered sympathetic discharge can elicit and exacerbate
ectopic neuronal activity from neuromas as well as at the
level of the DRG23. This could account for the frequent
exacerbation of phantom pain at times of emotional
distress24. Additional factors such as temperature, oxygenation level and local inflammation in neuromas and
associated DRGs might also have a role.
In animal studies, nerve injury-induced sensory–
sympathetic coupling with sympathetic sprouting into
the DRGs has been described, although the role of this
phenomenon in phantom limb pain is not clear18. In
some patients, the sympathetic maintenance of phantom limb pain is supported by evidence that systemic
adrenergic blocking agents sometimes reduce phantom
limb pain25. Similarly, injections of adrenaline into stump
neuromas have been shown to increase phantom limb
pain and paraesthesias in some amputees25. Although
sympathetically maintained pain does not necessarily
covary with regional sympathetic abnormalities, in some
patients sympathetic dysregulation in the residual limb
is apparent. For example, a microneurographic study of
sympathetic fibres in skin (but not deep somatic) nerves
in human lower limb amputees26 showed abnormal
sympathetic activity in the lower limb; however, none
of these individuals suffered from phantom limb pain.
It might be that deep somatic fibres could have a greater
role in phantom pain, although these were not studied here. So, damaged and reorganized nerve endings
together with an altered activity in the DRG represent a
potential source of pain and abnormal evoked activity in
nerve injury, including phantom limb pain.
root ganglion
Central changes: the spinal cord
Local anaesthesia of the stump or the plexus, or epidural
anaesthesia, do not eliminate ongoing phantom limb pain
in all amputees27,28; for example, 50% of the amputees in a
study involving anaesthesia of the brachial plexus27 were
pain-free, suggesting the involvement of more central
factors. Anecdotal evidence in human amputees was the
first to indicate that spinal mechanisms might have a
role in phantom limb pain. For example, during spinal
anaesthesia, phantom pains have been reported to occur
in patients who were pain-free at the time of the procedure29. Although direct evidence for spinal changes in
human amputees is lacking, experimental data based on
animal models of nerve injury are becoming available
that point towards an important role for CNS processes
in neuropathic pain.
Increased activity in peripheral nociceptors related
to inflammatory pain leads to an enduring change in the
synaptic responsiveness of neurons in the dorsal horn
of the spinal cord, a process known as central sensitization30. Central hyperexcitability similar to sensitization might also be triggered by nerve injury, as occurs
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Microglia
Glial cells are the ‘glue’ of the
nervous system, and support
and protect the neurons.
Microglia are a special form of
small glial cells; they have
immune functions and can be
involved in inflammatory
actions.
Substance P
A neuropeptide that plays an
important role in nociception
and is released by the primary
somatosensory afferents in the
spinal cord.
C-afferents
Unmyelinated fibres,
0.4–1.2 μm in diameter,
conducting nerve impulses
at a velocity of 0.7–2.3 ms–1.
They conduct secondary,
delayed pain.
Aδ afferents
Thinly myelinated nerve fibres
with a conduction velocity of
10–30 ms–1 that convey
nociceptive information to the
spinal cord. These receptors
convey first, sharp, pricking
pain and are located mainly on
hairy skin.
Aβ fibres
Large-diameter myelinated
fibres that have a conduction
velocity of ~40 ms–1 and
normally carry non-nociceptive
information.
during amputation. For example, spinal changes associated with nerve injury include increased firing of the
dorsal horn neurons, structural changes at the central
endings of the primary sensory neurons and reduced
spinal cord inhibitory processes31. Inhibitory GABA
(γ-aminobutyric acid)-containing and glycinergic
interneurons in the spinal cord could be destroyed by
rapid ectopic discharge or other effects of axotomy32, or
might change from having an inhibitory to an excitatory effect under the influence of brain-derived neurotrophic factor (BDNF) released from microglia33, thereby
contributing to a hyperexcitable spinal cord.
Another CNS process that might contribute to the
hyperexcitability of spinal cord circuitry following major
nerve damage is that of the downregulation of opioid
receptors, on both primary afferent endings and intrinsic
spinal neurons34. This is expected to add to disinhibition due to the reduction of normally inhibitory GABA
and glycine activity. In addition, cholecystokinin35, an
endogenous inhibitor of the opiate receptor, is upregulated in injured tissue, thereby exacerbating this effect
of disinhibition.
Changes that might trigger abnormal firing have
also been noted in ascending projection neurons from
the spinal cord to supraspinal centres. These changes
depend on the cascade of biological events that takes
place in the spinal cord after peripheral nerve damage. Part of this sensitization is due to, for example,
inflammation-induced facilitation of the response of
NMDA (N-methyl-d-aspartate) receptors to the primary
afferent neurotransmitter glutamate36. A remarkable
effect of the spinal changes evoked by nerve injury is
that low-threshold afferents can become functionally
connected to ascending spinal projection neurons that
carry nociceptive information to supraspinal centres.
Substance P is normally expressed only by C-afferents
and Aδ afferents, most of which are nociceptors. The
injury-triggered expression of substance P by Aβ fibres
could render them more like nociceptors. For example,
it might permit ectopic or normal activity in Aβ fibres
to trigger and maintain central sensitization. When this
happens, normally innocuous A-fibre input from the
periphery, ectopic input and input from residual intact
low-threshold afferents might contribute to phantom
pain sensation37.
Following peripheral nerve injury, degeneration of
central projection axons occurs. Massive deafferentation
is observed when dorsal roots are injured, or cut off from
the spinal cord. Deafferentation could act hand-in-hand
with the central effects of peripheral denervation to bring
about the changes that contribute to spinal hyperexcitability. A mechanism that might be of special relevance
to phantom phenomena is the invasion of regions of the
spinal cord that are functionally vacated by injured afferents. For example, in the neuroma model in rats and cats,
there is an expansion of receptive fields on skin adjacent
to the denervated part of the limb, and a shift of activity
from these adjacent areas into regions of the spinal cord
that previously served the part of the limb that was functionally deafferented by the nerve lesion38. In amputees
and patients with severed cervical nerve roots, signs of
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hyperexcitability can be demonstrated in dermatomes
adjacent to the denervated limb part, possibly indicating
the spread of spinal hyperexcitability from denervated
segments to segments immediately rostral and caudal to
the denervated zone (T.S.J. et al., unpublished observations). Such reorganization of the spinal map of the limb,
which could be due to the unmasking of previously silent
connections, is also reflected in brainstem and cortical
remapping (see below).
Central changes: brainstem, thalamus, cortex
A number of observations in amputees indicate that
supraspinal changes could be important. For example,
paraplegic individuals with high spinal cord injuries
can experience pain in the lower part of the body4,
although the relevance of this phenomenon for phantom pain after amputation is not clear. Moreover, spinal
anaesthesia does not always eliminate ongoing phantom limb pain28. In primates, the spinal cord forms only
2% of the CNS compared with 15% in rats39, suggesting an important role for supraspinal mechanisms in
plastic changes in the primate CNS. It is possible that
spinal changes contribute to supraspinal changes,
although the extent of the contribution is unclear.
Supraspinal changes related to phantom limb pain
involve the brainstem, thalamus and cerebral cortex.
For example, there is evidence that axonal sprouting in
the cortex is involved in the reorganizational changes
observed in amputated monkeys40. Thalamic stimulation and recordings in human amputees have revealed
that reorganizational changes might also occur at the
thalamic level and are closely related to the perception
of phantom limbs and phantom limb pain41. Studies
in monkeys have shown that changes in the cortex
might be relayed from the brainstem and thalamus42–45;
however, alterations at the subcortical level could also
originate in the cortex, which has strong efferent connections to the thalamus and lower structures 46,47.
FIGURE 1 summarizes the putative contributions of
peripheral, spinal and supraspinal processes in phantom
limb pain.
Cortical reorganization. New insights into phantom limb
pain have come from studies demonstrating changes in
the functional and structural architecture of the primary
somatosensory (SI) cortex subsequent to amputation and
deafferentation in adult monkeys. In these studies, the
amputation of digits in an adult owl monkey led to an
invasion of adjacent areas into the representation zone
of the deafferented fingers48, as revealed by microelectrode recordings. Pons et al.49 reported an even greater
cortical reorganization following deafferentiation of the
dorsal root (dorsal rhizotomy), with the representation
of the cheek in the SI cortex taking over the cortical arm
and hand representation in the range of centimetres.
On the basis of these findings, Ramachandran et al.50
suggested that referred sensations in the phantom (that
is, painful and non-painful phantom sensations that
can be elicited by stimulating body areas adjacent to
but also far removed from the amputated limb) are a
perceptual correlate of reorganizational processes in
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Normal
Reorganized
Central changes
• Unmasking
• Sprouting
• General disinhibition
• Map remodelling
• Loss of neurons and neuronal function
• Denervation
• Alterations in neuronal and glial activity
• Sensory–motor and sensory–sensory incongruence
Peripheral changes
• Structural changes in neurons and axons
• Ectopic impulses
• Ephaptic transmission
• Sympathetic–afferent coupling
• Down- and upregulation of transmitters
• Alterations in channels and transduction molecules
• Selective loss of unmyelinated fibres
Figure 1 | A schematic diagram of the areas involved in the generation of phantom limb pain and the main
peripheral and central mechanisms. The peripheral areas include the residual limb and the dorsal root ganglion, and
the central areas include the spinal cord and supraspinal centres such as the brainstem, thalamus, cortex and limbic
system. The proposed mechanisms associated with phantom pain are listed for the PNS and CNS.
the SI cortex (see also Cronholm51). In support of this,
they showed a point-to-point correspondence between
stimulation sites and areas of sensation from the mouth
to the phantom in arm amputees (that is, a “thumb in
cheek”52 map of stimulation sites on the face and corresponding sensation in the phantom hand). They called
this phenomenon topographical remapping, assuming
that it was based on parallel processes in the SI cortex.
However, it was shown that referred phantom sensations in arm amputees can be elicited from the toe53,
which is far removed from the representation of the arm
in the SI cortex, which suggests that other areas could be
involved in the generation of referred sensation.
It has been reported that topographical referred
phantom sensations occur in only a small percentage of
amputees54, whereas phantom limb pain is common; this
suggests that referred phantom sensation and phantom
pain might be related to different central processes.
Moreover, Halligan et al.55 showed that topographical
remapping can completely change over time. Imaging
studies have reported that upper extremity amputees
actually show a shift of the mouth into the hand representation in the SI cortex56,57. Another study58 provided
evidence that these cortical changes are less related to
referred phantom sensations, but rather have a close
association with phantom limb pain (FIG. 2). The larger
the shift of the mouth representation into the zone that
formerly represented the arm, the more pronounced
the phantom limb pain. These reorganizational shifts
in the SI cortex have been replicated in several studies54,59
and have also been described for the motor cortex60,61,
where a similar close association between map reorganization and the magnitude of phantom limb pain was
described62–64.
Computational models of deafferentation and related
phenomena have suggested that peripheral factors can
enhance the central reorganization of neuronal networks.
Therefore, abnormal noise-like input that might originate
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from a neuroma in the residual limb could greatly
enhance the amount of central map reorganization65.
Map reorganization might also be enhanced by the selective loss of C-fibres that occurs after amputation18, as
C-fibres seem to have a special role in the maintenance
of cortical maps66.
The extent of reorganizational changes along the
neuraxis might depend greatly on the developmental
stage of the CNS. The consequences of limb amputation
have been compared in the cortex, brainstem and dorsal
horn in adult and juvenile rats, and have shown that
amputation in adulthood leads mainly to cortical changes
whereas amputation at a younger age causes more comprehensive reorganization along the neuraxis67. Several
stages of cortical reorganization can be differentiated68,69.
The first relates to the unmasking of normally inhibited
connections. Unmasking of latent excitatory synapses
can be secondary to the increased release of excitatory
neurotransmitters, increased density of postsynaptic
receptors, changes in conductance of the neuronal
membrane, decreased inhibitory inputs or the removal
of inhibition from excitatory inputs70. The data suggest
that the excitatory activation could be the result of loss
of GABA-mediated inhibition71,72. In fact, several studies
have shown enhanced cortical excitability in patients with
phantom limb pain73,74. A second stage involves structural
changes such as axonal sprouting, as well as alterations in
synaptic strength. Finally, use-dependent plasticity might
lead to additional changes based on Hebbian learning and
long-term potentiation75.
Alterations in sensory and motor feedback. Research
into illusory perceptions, such as the perception of body
ownership of a rubber hand76 (BOX 1) has shown that not
only the SI cortex but also frontal and parietal areas are
involved in the perception of abnormal somatosensory
phenomena, and might also have a role in phantom
sensation and phantom pain. It has been suggested that
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Phantom limb pain
Amputees without pain
Healthy controls
Figure 2 | Cortical changes related to phantom limb pain. Functional MRI data from
seven patients with phantom limb pain, seven amputees without pain and seven healthy
controls during a lip pursing task. Activation in primary somatosensory and motor
cortices is unaltered in amputees without pain and is similar to that of healthy controls. In
the amputees with phantom limb pain the cortical representation of the mouth extends
into the region of the hand and arm. Reproduced, with permission, from REF. 64 © (2001)
Oxford Univ. Press.
abnormal painful sensations might be related to the
incongruence of motor intention and sensory feedback
and a corresponding activation of frontal and parietal
brain areas77. In line with this suggestion, one study used
a mirror to create a discrepancy between actual and seen
movement (movement seen in the mirror is discrepant
from the movement behind the mirror if both arms
perform asynchronous movements) 78. The authors
reported the presence of painful and non-painful
paraesthesias as a consequence of the incongruent
movement condition and suggested that sensorimotor
incongruence might cause the abnormal sensations seen
in many neuropathic pain syndromes. However, it has
been pointed out that this was not a controlled study, and
that the role of these central disturbances in perceptual
and motor processing for phantom pain and phantom
phenomena remains to be determined79.
Telescoping is another phenomenon that is frequently observed in amputees and refers to perceived
changes in the size and length of the phantom, which
can even retract into the stump (FIG. 3) . Whereas
telescoping was previously thought to be a sign of adaptive plasticity, it is actually related to increased levels of
phantom pain54. The research into illusory perceptions
and imagery in other sensory domains has shown that
the primary cortical areas respond to the perceived and
not the actual input into the respective sensory system80.
Extended phantoms might therefore provide ongoing
motor and sensory feedback to the area that previously
represented the amputated limb, whereas telescoped
phantoms activate areas remote from the limb representation. So, the continued perception of extended
phantoms might reverse maladaptive cortical changes.
Functional MRI data from subjects with varying degrees
of telescoping show that the cortical representation of
the phantom movement actually follows the location
of the perceived movement and is not statically fixed in
the cortical representation zone of the hand (H.F. et al.,
unpublished observations) (FIG. 3). These data support
the notion that visual, sensory and motor feedback to the
cortex might be an important determinant of phantom
NATURE REVIEWS | NEUROSCIENCE
limb phenomena and pain that needs to be further investigated. These hypotheses might also be important for
our understanding of chronic painful and non-painful
symptoms in both neuropathic and other types of pain
in general.
The pain memory hypothesis. Sometimes pain in the
phantom is similar to the pain that existed in the limb
prior to amputation. The likelihood of this ranges from
10–79% in different reports, and depends on the type
and time of assessment81,82. It has been proposed that
pain memories established prior to the amputation
are powerful elicitors of phantom limb pain83,84. Pain
memories might be implicit; the term implicit pain
memory refers to central changes related to nociceptive input that lead to subsequent altered processing of
the somatosensory system and do not require changes
in conscious processing of the pain experience85. In
patients with chronic back pain, it was shown that
increasing chronicity is correlated with an increase in
the representation zone of the back in the SI cortex, and
it was also reported that the experience of acute pain
alters the map in the SI cortex86. These data indicate
that long-lasting noxious input might lead to long-term
changes at the central, and especially at the cortical,
levels that affect the later processing of somatosensory
input.
It has long been known that the SI cortex is involved
in the processing of pain and that it might be important for the sensory–discriminative aspects of the pain
experience87. There have also been reports that phantom
limb pain was abolished after the surgical removal of
portions of the SI cortex, and that stimulation of this
area evoked phantom limb pain88,89. If a somatosensory
pain memory has been established with an important
neural correlate in spinal and supraspinal structures,
such as in the SI cortex, subsequent deafferentation and
an invasion of the amputation zone by neighbouring
input might preferentially activate neurons that code
for pain. As the cortical area that receives input from
the periphery seems to stay assigned to the original zone
of input, the activation in the cortical zone representing
the amputated limb is referred to this limb and could
be interpreted as phantom sensation and phantom limb
pain90.
Several prospective studies82,91 have shown that chronic
pain before the amputation predicts later phantom
limb pain, therefore supporting the pain memory hypothesis. However, these samples included few traumatic
amputees and mainly amputees with long-standing prior
pain problems, in whom pain memories can have developed over a long time period. In traumatic amputees,
additional factors relating to the surgery, such as type of
anaesthesia, and pre- and postoperative pain, could be
important. Nevertheless, the pain memory hypothesis
is also supported by the relatively modest effects of preemptive analgesia92. On the basis of the idea that the afferent barrage of nociceptive input might not be sufficiently
inhibited by central anaesthesia, peripheral anaesthesia
is added for some time before and during surgery to
prevent central sensitization from occurring93. However,
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Box 1 | Incongruence phenomena, bodily symptoms and illusory perceptions
In recent years, the preconditions and neural correlates of a number of illusory somatosensory phenomena have been
investigated and might shed light on the understanding of phantom phenomena and phantom pain. Sensory illusions such
as the tactile funnelling illusion80, during which the simultaneous presentation of brief stimuli at multiple points on the skin
produces a single focal sensation at the centre of the stimulus pattern even when no physical stimulus occurs at that site,
have been shown to have a percept-related and not a stimulation-related representation in the primary somatosensory (SI)
cortex. These data not only indicate that the brain processes the perceptual, and not the physical, properties of sensory
stimulation but also that these integrative processes occur early in the SI cortex.
Illusory phenomena, however, involve additional brain regions when the perception of the body and of individual body
parts is involved, as in phantom sensations. Here, bottom-up processes of visuotactile integration and top-down processes
that originate from the representation of one’s own body are important in generating illusions of body ownership, such as
in the rubber hand illusion. In this illusion, synchronous input from the actual and the rubber hand, related to synchronous
stroking of the actual and the fake hand, produce the feeling of ownership of the artificial hand113. If the rubber hand is in
an implausible position with respect to the normal body schema, the illusion does not occur. Whereas synchronous
stimulation can lead to the illusion of body ownership, asynchronous stimulation in one sensory modality or between the
senses can lead to abnormal sensory perception78 and mismatch-related activations in ventral premotor and parietal
regions114. The extent to which the restoration of homeostatic processes and of an intact body schema takes part in these
perceptual phenomena needs to be determined115. The exploration of the preconditions and neural correlates of such
illusory perceptions might shed light on the experience of phantom phenomena and unusual bodily sensations,
somatosensory misperceptions and phantom pain.
a controlled study in amputees showed that pre-emptive
analgesia did not significantly reduce the incidence of
phantom limb pain94, although the addition of an NMDA
receptor antagonist in the peri-operative phase extending into the postoperative weeks might have beneficial
results95. This effect could be due to the erasure of preexisting, and the prevention of postoperatively acquired,
somatosensory pain memories. The fact that pre-existing
sensitivities in the processing of nociceptive stimulation
might be important is also underscored by the finding
that pain pressure thresholds before the amputation
predict phantom limb pain after the amputation96. To our
knowledge, no study has examined the extent to which
prior pain experience in general might contribute to
phantom limb pain. Research on pain experiences in the
perinatal phase has shown that sensitization occurs that
could then predispose individuals to chronic pain development97,98. Later life experience and modelling might
have similar effects. The role of insufficient postoperative
pain management has so far probably been underestimated99, and more longitudinal research is needed to test
the pain memory hypothesis.
Myoelectric prosthesis
A motor-driven prosthesis that
can, for example, be used for
grip movements and is
operated through the use of
electromyographic signals from
muscles.
Affective and motivational aspects of pain. It is likely
that reorganization following amputation occurs not
only for the areas involved in sensory–discriminative
aspects of pain, but also for those brain regions that
mediate affective–motivational aspects of pain, such
as the insula, anterior cingulate and frontal cortices100.
A close relationship has been shown between activation of the anterior cingulate cortex and phantom limb
pain after induced phantom pain by hypnotic suggestion101. Another study observed a potentiation of
sensory responses in the anterior cingulate cortex of
rats following limb amputation102. The role of affective and motivational factors in phantom limb pain is
also underscored by the fact that several studies could
predict the severity of phantom limb pain from depression and coping-related variables8. These factors need
to be explored in greater detail.
878 | NOVEMBER 2006 | VOLUME 7
Implications for the treatment of phantom pain
Several studies, including large surveys of amputees, have
shown that most currently available treatments for phantom limb pain, which range from analgesic and antidepressant medication to stimulation, are ineffective and fail
to consider the mechanisms that underlie production of
the pain83. On the basis of the findings on CNS plasticity
related to phantom pain, experimental methods that affect
neuroplasticity as well as memory formation and maintenance might positively influence phantom limb pain.
Work in healthy animals and humans on stimulationinduced plasticity has shown that extensive, behaviourally
relevant stimulation of a body part leads to an alteration
of its cortical representation zone103,104. In patients with
phantom limb pain, intensive use of a myoelectric prosthesis
is positively correlated with both reduced phantom
limb pain and reduced cortical reorganization105. When
cortical reorganization was partialled out, the relationship between prosthesis use and reduced phantom limb
pain was no longer significant, suggesting that cortical
reorganization mediates this relationship. An alternative
approach in patients in whom prosthesis use is not viable
is the application of behaviourally relevant stimulation.
A 2 week regimen that consisted of daily discrimination training of electrical stimuli to the stump led to
significant improvements in phantom limb pain and
a significant reversal of cortical reorganization as assessed
with neuroelectric source imaging106. A control group of
patients who received standard medical treatment and
general psychological counselling in this time period did
not show similar changes in cortical reorganization and
phantom limb pain. The basic idea of the treatment was
to provide input into the amputation zone and thereby
undo the reorganizational changes that occurred subsequent to the amputation. This effect was replicated by
asynchronous stimulation of the mouth and stump in
upper extremity amputees107.
Similar effects on phantom pain and cortical activation were reported for imagined movement of the phantom108. Mirror treatment (where a mirror is used to trick
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Imagined movement
100
Telescoping (%)
75
50
25
r = 0.85
IM
0
EM
0
2
4
6
8
10
12
14
16
Shi of S1 activation towards Cz (mm)
Figure 3 | Brain correlates of the telescoping phenomenon. The
phenomenon of telescoping refers to the shrinking and retraction of the
phantom towards the residual limb (left). The middle panel shows brain
activation related to the imagined movement (IM) of telescoped and
non-telescoped phantoms. The representation of the movement in the
primary somatosensory (SI) cortex (red shading) follows the perceived
location of the movement (opening and closing of the hand) and not the
actual anatomical location (hand area). Completely telescoped
phantoms create activity in the cortical region that represents the
shoulder, partially telescoped phantoms in the region of the arm and
non-telescoped phantoms in the hand region. EM denotes the cortical
activation related to executed movements of the intact hand and
Complex regional pain
syndrome
(CRPS). A chronic neuropathic
pain syndrome of two types.
CRPS1 occurs most often in
the arms or legs after a minor
or major injury and is
accompanied by severe pain,
swelling, oedema, sudomotor
abnormalities and increased
sensitivity to touch. CRPS2 is
related to an identified nerve
injury.
1.
2.
3.
4.
5.
indicates where the representation of the hand in the SI cortex is located.
The right panel shows the correlation coefficient that was computed for
the amount of telescoping (0–100%) and the activation related to the
perceived movement of the phantom in the SI cortex with the distance of
the maximally activated voxels from the central midline position of the
cortex (Cz) computed in millimetres. The correlation was significant in
the SI, but not in the primary motor cortex (blue shading). This indicates
that pain-free amputees might experience reactivation of the
deafferented cortical representation zone related to that hand, whereas
amputees without pain might not, which could be related to their pain.
The data also indicate that this effect might originate directly in the SI
cortex, and is not mediated by the motor cortex.
the brain into perceiving movement of the phantom
when the intact limb is moved) might be effective but has
so far been tested only in an anecdotal manner for phantom limb pain109,110, although it effectively reduces pain
in complex regional pain syndrome111. Pharmacological
interventions that target either neuroplastic changes or
memory mechanisms (which have overlapping targets)
should also be effective. These might include NMDA
receptor antagonists, GABA agonists or anticonvulsive
agents, to mention only a few options. Stimulation of
cortical areas that are hyperactive by transcranial magnetic stimulation or direct current stimulation might
also be viable options112. These approaches are based on
the idea that cortical hyperexcitability, which contributes
to pain, could be reduced by setting a ‘virtual’ lesion in
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Acknowledgements
This article is dedicated to the memory of T. Pons, whose work
inspired many of the findings reported here. This work was
supported by the Deutsche Forschungsgemeinschaft, the
Bundesministerium für Bildung und Forschung (German
Neuropathic Pain Network) and the Lundbeck Foundation,
Denmark. The authors would like to thank W. Jänig for helpful
comments on an earlier version of this article and M. Lotze
for help with the figures.
Competing interests statement
The authors declare no competing financial interests.
FURTHER INFORMATION
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